When certain halogenated pyrimidines such as bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) are incorporated into cellular DNA, cells become more sensitive to ionizing radiation and chemotherapy drugs. This observation has led to several clinical studies over the years and recently at the NCI to evaluate whether selective sensitization of tumors could be achieved by IdUrd infusion followed by radiation. Phase I studies have been completed. We were not able, within the context of our protocol, to show a role for high dose hyperfractionation and continuous IV infusion of IdUrd in brain tumors. Our laboratory has been able to give us some possible explanations for these results. Thymidine replacement in tumor cell DNA has been evaluated from 4 patients who received IdUrd infusion for 5-7 days prior to surgery. Replacement values ranged from 0-4%. In vitro studies would suggest that replacement values about 6-10% are required to observe significant radiosensitization. High local control rates in large unresectable sarcomas treated with high dose radiation/IdUrd has been confirmed in a more extensive study. We are now randomizing patients with unresectable sarcomas without metastatic disease to receive the halogenated pyrimidine IdUrd as a radiosensitizer. IdUrd replacement data from this set of patients has thusfar revealed much higher replacement values (7.3-14.2%) than was seen for gliomas. Other patients such as gliomas and unresectable head and neck cancers are being treated on a non-randomized basis at this time, with clinical-laboratory interaction to obtain labeling and uptake information. In a small group of head/neck patients IdUrd replacement values have ranged from 2.9-9.1 perhaps explaining the dramatic tumor response observed in these patients.